Rituximab in Lymphoma Associated Auto-Immune Haemolytic Anemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4923-4923
Author(s):  
Amit Bhargava ◽  
Nirupma Banerjee
Keyword(s):  
B Cells ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Carbohydrate Antigen ◽  
Genetically Engineered ◽  
Cold Agglutinin ◽  
Cold Agglutinins ◽  
Clonal Proliferation

Abstract Abstract 4923 The association of Autoimmune hemolytic and Non Hodgkin's lymphoma is a known phenomenon. Cold hem agglutinin disease (CHD), is an uncommon Autoimmune hemolytic anemia, mediated by cold reactive auto antibodies that bind to erythrocyte carbohydrate antigen causing hem agglutination and complement mediated hemolysis. Cold agglutinin–mediated hemolysis occurs at low temperature which may be severe and difficult to treat. CHD may be primary when it is idiopathic or secondary as in lympho-proliferative disorder of bone marrow associated with clonal proliferation of CD20 B cells that produce monoclonal 1g M cold agglutinin (kappa /lamda). Rituximab has been used as an as a novel treatment option in Autoimmune hemolytic anemia. Rituximab is a genetically engineered chimeric monoclonal antibody that targets the CD20 antigen on B cells. Rituximab in autoimmune conditions possibly acts by destruction of CD20_clonotypic precursor B cells and/or CD20 plasma cells, thus is effective in controlling immunoglobulin-mediated diseases of B lymphocytes. We analysed four patients of lymphoma with severe CHD who were successfully treated with the chimeric anti-CD20 monoclonal Rituximab (375mg/ m2) intravenously every three weeks for four to six cycles, till the Agglutinins disappeared from the serum. Patient and method In this study patients diagnosed with lymphoma associated CHD were treated with Rituximab with a dose of 375mg/ meter square given every three weeks for four to six cycles, till the primary aim was achieved. The primary aim was correction of anemia, disappearance of cold hem-agglutinins from serum, assessed by complete blood counts and measuring cold agglutinins in serum. Four such patients were studied, all of them had NHL-DLBCL (IHC proven), with severe hemolysis and jaundice with Hemoglobin <5 gm/ dl. All had presence of cold agglutinins in the serum and were positive for direct and indirect coomb's test. Response All the patients showed significant improvement in the symptoms due to anemia and there was a rise in hemoglobin detected within the first week of Rituximab treatment. They achieved normal levels of hemoglobin with four to six weeks of treatment and in three patients cold agglutinins disappeared after completion of five cycles and the fourth patients had it after the sixth cycle. None of the patients was given any transfusion because of incompatibility issues. Conclusion Our experience with Rituximab was excellent in this indication and patients had a good overall outcome. Further trials need to be done for more evidence in this regard. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Anna Zaninoni ◽  
Juri A. Giannotta ◽  
Anna Gallì ◽  
Rosangela Artuso ◽  
Paola Bianchi ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Plasma Cell ◽  
Clinical Efficacy ◽  
Lupus Erythematosus ◽  
Autoimmune Hemolytic Anemia ◽  
Plasma Cells ◽  
Proteasome Inhibitors ◽  
Immunomodulatory Effect ◽  
Cold Agglutinin ◽  
Cold Agglutinin Disease

Daratumumab is a monoclonal antibody directed against the transmembrane glycoprotein CD38 expressed on plasma cells and lymphoplasmocytes, with a proven efficacy in multiple myeloma. Here we show its clinical efficacy in a patient with cold agglutinin disease (CAD) relapsed after multiple lines of therapy. CAD is caused by cold reactive autoantibodies that induce complement mediated hemolysis and peripheral circulatory symptoms. The disease is also characterized by the presence of monoclonal IgM gammopathy and of a lymphoid bone marrow infiltration that benefits from B-cell targeting therapies (i.e., rituximab) but also from plasma cell directed therapies, such as proteasome inhibitors. In the patient described, we also show that daratumumab therapy influenced the dynamics of several immunoregulatory cytokine levels (IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β) indicating an immunomodulatory effect of the drug beyond plasma cell depletion. In addition, we provide a literature review on the use of daratumumab in autoimmune conditions, including multi-treated and refractory patients with autoimmune hemolytic anemia (both CAD and warm forms), Evans syndrome (association of autoimmune hemolytic anemia and immune thrombocytopenia) and non-hematologic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

scholarly journals Most CD5+ B Lymphocytes Secrete IL-10 in Autoimmune Hemolytic Anemia/Evans Syndrome Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4887-4887
Author(s):  
Limin Xing ◽  
Manjun Zhao ◽  
Hongli Zhu ◽  
Zonghong Shao
Keyword(s):  
B Cells ◽  
Serum Level ◽  
B Lymphocytes ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Enzyme Linked Immunosorbent Assay ◽  
Newly Diagnosed ◽  
Evans Syndrome

Abstract Objective: Autoimmune hemolytic anemia (AIHA)/Evans syndrome is a form of immune-related cytopenia characterized by autoantibodies directed against red blood cells. A subset of B lymphocytes expressing CD5 is found in patients with AIHA/Evans syndrome. Previous studies have shown that the number of CD5+ B lymphocytes is correlated with the severity of AIHA/Evans syndrome. IL-10 can be induced in various types of human B cells, including naive, memory, and CD5+B cells, following B-cell activation by Th-cell-dependent and TLR-dependent signals. This study is to investigate the secretion function of CD5+ B lymphocytes in AIHA/Evans syndrome (ES) patients. Methods: 25 untreated AIHA/ES patients, 28 remission AIHA/ES patients and 25 healthy controls (HCs) were enrolled in this study. The quantity of CD5+B lymphocytes which produce interleukin-10 (IL-10) (CD5+IL-10+) were detected by flow cytometry. CD5+ B lymphocytes were sorted from Peripheral blood (PB) by CytoFLEX Flow Cytometer. The expression of IL-10 mRNA in CD5+ B cells were measured by real-time PCR (RT-PCR). The concentrations of IL-10 in serum were detected by Enzyme-linked Immunosorbent assay (ELISA). Results: The percentage of CD5+IL-10+B cells in CD5+ B lymphocytes in newly diagnosed patients was 82.18±14.78%, which being significantly higher than that of remission AIHA/ES patients (56.68±24.39%) and HC (51.90±22.95%)(p<0.05). The percentage of CD5+IL-10+ B cells in CD5+ B lymphocytes in newly diagnosed patients was negatively correlated with their serum level of hemoglobin, C3 (P<0.05) and positively correlated with their serum level of LDH, TBIL and IBIL (P<0.05). The expression level of CD5+ B lymphocytes IL-10 mRNA in newly diagnosed patients (49.34±22.84) was higher than that of remission patients (3.97±3.83) and HC (1.78±1.66) (P<0.05). The concentration of IL-10 in serum in newly diagnosed patients (4.01±1.54 pg/ml) was lower than that of remission patients (5.08±1.72pg/ml) and HC (5.70±1.60pg/ml) (P<0.05). Conclusions: Most CD5+ B lymphocytes secrete IL-10 in AIHA/Evans patients and are positively correlated with the severity of the disease. The increased quantity of CD5+IL-10+ B cells and the decreased cytokines-secreted level maybe involved in the occurrence of AIHA/Evans syndrome. Disclosures No relevant conflicts of interest to declare.

scholarly journals Expression of Activated Molecules on CD5+ b Cells in Autoimmune Hemolytic Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4765-4765
Author(s):  
Hongli Zhu ◽  
Limin Xing ◽  
Hong Liu ◽  
Huaquan Wang ◽  
Rong Fu ◽  
...  
Keyword(s):  
B Cells ◽  
B Lymphocytes ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Conflicts Of Interest ◽  
Newly Diagnosed ◽  
Evans Syndrome ◽  
Hla Dr ◽  
Significant Difference ◽  
Normal Controls

Abstract Objective To detect the percentage of CD5+ B cells in peripheral blood (PB) of patients with autoimmune hemolytic anemia (AIHA) /Evans syndrome and the expression of active molecules on CD5+ B cells. Methods The expressions of CD80, CD86, CD69 and HLA-DR on CD5+ B cells in PB of 25 cases with AIHA/Evans syndrome, (11 newly diagnosed, 14 remission) and 14 normal controls were detected by flow cytometry. Results (1) The percentage and the quantity of CD19+ B cells in newly diagnosed patients were [(22.78±19.77)%, (34.47±22.88)×107/L] respectively, which were obviously higher than those of remission patients [(6.80±5.47)%,(10.09±7.69)×107/L] and normal controls [(7.76±2.6)%,(10.03±3.31)×107/L](p<0.05), but there was no significant difference between the latter two groups. (2)The percentage of CD5+ B cells in B cells of untreated patients was [(27.44±18.43) %], which was higher than that of normal controls [(13.49±6.95) %, P=0.008]. The percentage of CD5- B cells of untreated patients and normal controls were [(72.56±18.43) %], [(83.92±11.46) %] and there was no significant difference. (3)CD80 on CD5+ B cells of untreated patients was [(46.04±26.93)%], which was obviously higher than that of remission patients [(8.82±8.78)%,P=0.003] and normal controls [(6.27±4.87)%,P=0.002], the latter two groups had no significant difference. There was no significant difference of CD80 on CD5- B cells among the three groups. CD86 on CD5+ B cells of untreated patients was [(37.37±24.18)%], which was significantly higher than that of remission patients [(16.53±10.31)%,P=0.004] and normal controls [(14.90±9.62)%,P=0.029], the latter two groups had no significant difference. But CD86 on CD5- B cells are similar in the three groups and there was no difference. CD69 on CD5+ B cells of newly diagnosed patients was (median: 5.77%), which was higher than that of remission patients (3.34%) and normal controls(4.01%), but without any significant difference within three groups. CD69 on CD5- B cells showed no significant difference among three groups. HLA-DR on CD5+ B cells and CD5- B cells showed no significantly difference within three groups. (4)The expression of CD80[(46.04±26.93)%] and CD86[(37.37±24.18)%] on CD5+ B cells were higher than those on CD5- B cells [(22.57±10.54)%,P=0.016], [(17.92±16.27)%,P=0.006]. The expression of CD69 (median: 5.77%) on CD5+ B cells was higher than that of on CD5- B cells (median: 1.20%), but without significant difference. The expression of HLA-DR on CD5+ B cells and CD5- B cells had no significant difference. (5)The expression of CD80 on CD5+ B cells [(8.82±8.78) %] was lower than that of on CD5- B cells [(28.68±18.59) %, P=0.001]. The expression of CD86, CD69 and HLA-DR on CD5+ B cells and CD5- B cells showed no significant difference. (6)The expression of CD80 on CD5+ B cells [(6.27±4.87)%] was lower than that of on CD5- B cells [(27.54±9.42)%,P<0.05]. The expression of CD86ACD69 and HLA-DR on CD5+ B cells and CD5- B cells had no significant difference. Conclusions The percentage and quantity of B lymphocytes in PB of AIHA/Evans syndromes patients increased. CD5+ B lymphocytes are mainly cells and CD80 and CD86 on CD5+ B cells went up. The activated molecules on cell surface may be the basis of the different function of CD5+ and CD5- B lymphocytes. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia in Association with Antiphospholipid Syndrome

2021 ◽  
pp. 1-4
Author(s):  
Ram Gelman ◽  
Fadi Kharouf ◽  
Yuval Ishay ◽  
Alexander Gural
Keyword(s):  
Hemolytic Anemia ◽  
Antiphospholipid Syndrome ◽  
Complement Activation ◽  
Autoimmune Hemolytic Anemia ◽  
Cold Agglutinin ◽  
Primary Antiphospholipid Syndrome ◽  
Unique Case ◽  
Hematologic Disorders ◽  
Clear Association ◽  
Immune Mediated

Antiphospholipid syndrome and cold agglutinin-mediated autoimmune hemolytic anemia are 2 distinct immune-mediated hematologic disorders. While no clear association exists between these 2 entities, complement activation is known to occur in both of them. Herein, we report a unique case of cold agglutinin hemolytic anemia in a patient with a known primary antiphospholipid syndrome.

Establishment of An Angioimmunoblastic T-Cell Lymphoma (AITL) Model in the NOG Mouse

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5207-5207
Author(s):  
Asahi Ito ◽  
Takashi Ishida ◽  
Fumihiko Sato ◽  
Fumiko Mori ◽  
Ayako Masaki ◽  
...  
Keyword(s):  
B Cells ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Treatment Modalities ◽  
Medium Size ◽  
Double Immunostaining ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Novel Treatment ◽  
Nog Mice

Abstract Abstract 5207 The aim of the present study was to establish a murine AITL model. We inoculated cells from affected LN of an AITL patient intraperitoneally into NOG mice. Hepatosplenomegaly developed in these animals about 2 months later, and normal splenic architecture was replaced by multi-focal deposit of lymphocytes and numerous blood vessels. Some of the former consisted of AITL cells characterized by small to medium size, and clear to pale cytoplasm. The remaining lymphocytes were non-neoplastic reactive cells including CD8-positive cells, B cells, and plasma cells. Double immunostaining revealed that the neoplastic cells were positive for both UCHL-1 (CD45RO) and BCL-6. In addition, significant levels of human IgG/A/M were detected in these animals. The AITL cells engrafted in the NOG mice indeed functioned as follicular helper T (Tfh) cells and induced antibody production by B-cells, consistent with recent evidence that AITL is a neoplasm originating from Tfh cells. These clinical and histological features in the mice are almost identical to those seen in AITL patients. Cells from spleens of affected animals could be serially transplanted, with enrichment of the AITL cells together with reduction of the reactive cells at each passage. This phenomenon might reflect the progressive nature of AITL. TCRB analysis demonstrated that the AITL clone in the mice was identical to that from the donating patient. This is the first mouse model of AITL, and could be a powerful tool for investigating, and developing novel treatment modalities for this type of lymphoma. Disclosures: No relevant conflicts of interest to declare.

Clinical Heterogeneity Of Autoimmune Hemolytic Anemia: A 35-Years Retrospective Study Of 157 Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3428-3428
Author(s):  
Wilma Barcellini ◽  
Bruno Fattizzo ◽  
Tommaso Radice ◽  
Anna Zaninoni ◽  
Nicoletta Revelli ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Conflicts Of Interest ◽  
Acute Infection ◽  
Thermal Characteristics ◽  
Response Rates ◽  
Cytotoxic Drugs ◽  
Clinical Heterogeneity ◽  
Life Threatening

Abstract The clinical presentation of autoimmune hemolytic anemia (AIHA) is greatly heterogeneous, from mild/compensated to life-threatening forms. The aim of this study was to correlate the clinical and serological characteristics of the disease, usually classified as warm (WAIHA), cold (CHD), and mixed, based on the thermal and isotype characteristics of the anti-RBC antibody (IgG, IgM or both, respectively). One-hundred fifty seven AIHA patients (61 M and 96 F, median age 57, range 5-95) referred to our institution from 1978 to September 2012 were investigated. They had been followed-up for a median of 26 months (range 12-271), and 50% were still in follow-up. As regards the thermal characteristics 40% of cases were WAIHA, 32% CHD, 19% mixed forms and 9% atypical (12 DAT negative and 1 DAT positive for IgA only). Considering the severity of anemia at onset 33% of cases had Hb levels<6 g/dl, 34% Hb 6-8 g/dL, 18% Hb 8-10 g/dL, and 15% Hb>10 g/dL. The most severe AIHA cases were mainly mixed (18/30, 60% p=0.001) and atypical (6/13, 46%) forms, whereas only a small fraction of CHD was characterized by a severe onset (8/51, 16% p=0.002). Reticulocytopenia (<100.000 mmc) was more frequently observed in cases with severe onset (14/52, 27%), possibly contributing to the clinical picture. Eleven patients experienced an acute event at the onset of hemolysis and the majority of them (7/11, 63% ) were WAIHA; we recorded 4 deep venous thrombosis (with 2 subsequent pulmonary embolisms), 1 disseminated intravascular coagulation, 3 cardiac ischemic events, 2 acute renal failure and 4 acute infection (3 pneumonias and 1 sepsis); 18 patients died because of AIHA during the follow up. As regard therapy, we considered steroids, splenectomy, cytotoxic drugs and rituximab: 45% of cases (mostly WAIHA) were treated with steroids only, 23% with 2 lines, 10% with 3, and 6% with 4 or more lines; splenectomy was performed in 20 cases, mostly mixed and severe forms (p=0.001); 23 patients were treated with various cytotoxic drugs, and 33 with rituximab (the latter was more frequently administered in clinically severe cases, and in mixed and atypical forms, p=0.009). On the whole, the most severe patients were those who underwent 3 or more lines of therapy, compared with the other cases (14/52 versus 11/105, p=0.015). Finally, 16% of cases have never been treated, mostly CHD with mild anemia. Transfusions were performed in 65 cases, plasma-exchange in 3 (all with Hb<6 g/dL), and erythropoietin administered in 6 cases. Of note, the presence of an Hb value lower than 6 g/dL at onset was a risk factor for the requirement of 3 or more lines of therapy (odds ratio 3.148, CI 95% 1.312-7.552). Response rates to steroid therapy were similar in warm, cold, mixed and atypical AIHAs (on average 70%). Responses to rituximab were similar in cold and other AIHA forms (70-80%). Splenectomy, was ineffective in the 2 CHD who underwent surgery, whereas response rates were 63% in WAIHA and 80% in mixed and atypical cases. In conclusion, AIHAs showed a marked clinical heterogeneity, 1/3 of cases with a severe onset and with life threatening complications. These cases are frequently mixed or atypical forms and refractory to different therapies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Engineering of Primary Human B cells with CRISPR/Cas9 Targeted Nuclease

2018 ◽  
Author(s):  
Matthew J. Johnson ◽  
Kanut Laoharawee ◽  
Walker S. Lahr ◽  
Beau R. Webber ◽  
Branden S. Moriarity
Keyword(s):  
B Cells ◽  
Genome Engineering ◽  
Plasma Cells ◽  
Basic Research ◽  
Genetically Engineered ◽  
Nucleic Acid Delivery ◽  
Human B Cells ◽  
Site Specific Integration ◽  
Cas9 Protein ◽  
Donor Template

AbstractB cells offer unique opportunities for gene therapy because of their ability to secrete large amounts of protein in the form of antibody and persist for the life of the organism as plasma cells. Here, we report optimized CRISPR/Cas9 based genome engineering of primary human B cells. Our procedure involves enrichment of CD19+ B cells from PBMCs followed by activation, expansion, and electroporation of CRISPR/Cas9 reagents. We are able expand total B cells in culture 10-fold and outgrow the IgD+IgM+CD27- naïve subset from 35% to over 80% of the culture. B cells are receptive to nucleic acid delivery via electroporation 3 days after stimulation, peaking at Day 7 post stimulation. We tested chemically modified sgRNAs and Alt-R gRNA targeting CD19 with Cas9 mRNA or Cas9 protein. Using this system, we achieved genetic and protein knockout of CD19 at rates over 70%. Finally, we tested sgRNAs targeting the AAVS1 safe harbor site using Cas9 protein in combination with AAV6 to deliver donor template encoding a splice acceptor-EGFP cassette, which yielded site-specific integration frequencies up to 25%. The development of methods for genetically engineered B cells opens the door to a myriad of applications in basic research, antibody production, and cellular therapeutics.

scholarly journals Autoimmune Hemolytic Anemia and Checkpoint Inhibitors: 68 Cases from the FDA Database and Critical Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2324-2324
Author(s):  
Georges Tanios ◽  
Peter B Doley ◽  
Reinhold Munker
Keyword(s):  
Lung Cancer ◽  
Malignant Melanoma ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
High Frequency ◽  
Conflicts Of Interest ◽  
Checkpoint Inhibitors ◽  
Chemotherapy Drugs ◽  
Aggressive Management ◽  
Time Period

Abstract Immune checkpoint inhibitors (CPI) are widely used in modern oncology and have improved the prognosis of lung cancer, bladder cancer, malignant melanoma and other malignancies. Unlike cytotoxic chemotherapy, drugs like nivolumab, pembrolizumab and ipilimumab are associated with a high frequency of immune-related adverse effects. We recently observed a patient with lung cancer who developed a fulminant warm-antibody autoimmune hemolytic anemia (AIHA) and reviewed the literature and public databases of the Food and Drug Administration (FDA) to help understand the association between CPI use and AIHA. A total of 68 cases of AIHA were identified in the FDA database during the time period 2012-2018; 43 associated with nivolumab, 13 with pembrolizumab, 7 with ipilimumab and 5 with atezolizumab administration (see Table 1). All episodes of AIHA were listed as serious. If the total number of adverse effect cases reported to the FDA is taken as a reference, AIHA is rare, but occurred more frequently with PD-1 or PDL1 targeting agents (0.15 to 0.25%) than with CTLA4-inhibitors (0.06%). The underlying cancer diagnoses corresponded mostly to the approved indications for CPI (32 cases of malignant melanoma, 24 cases of lung cancer). In about a quarter of cases with AIHA other immune related side effects were reported. In addition to our case, the literature review identified 10 similar cases. AIHA can occur earlier and later after the administration of CPI (median of 10 weeks, range 2- 78). Most cases of AIHA responded to steroids, but 2/11 were fatal. In conclusion, we describe AIHA as a rare and serious immune-related side effect of checkpoint inhibitors. Because of its seriousness and the underlying comorbidities, early aggressive management is necessary. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cold agglutinin-mediated autoimmune hemolytic anemia associated with COVID-19 infection

2021 ◽  
Author(s):  
Chee Yik Chang ◽  
Huang Hin Chin ◽  
Pek Woon Chin ◽  
Masliza Zaid
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Supportive Therapy ◽  
Blood Film ◽  
Cold Agglutinin ◽  
Cell Agglutination ◽  
Negative Results ◽  
Systemic Corticosteroids ◽  
Packed Cell Transfusion ◽  
Oropharyngeal Swab

Abstract Cold agglutinin-mediated autoimmune hemolytic anemia (AIHA) is a rare disorder associated with COVID-19 infection. Here, we present a case of COVID-19 pneumonia with concomitant cold agglutinin syndrome (CAS). On admission, the patient was anemic with reticulocytosis and the direct antiglobulin test showed the presence of anti-complement (C3d) antibodies. Peripheral blood film demonstrated red cell agglutination which was dispersible on blood warming. Chest radiography showed bilateral lower zone ground glass appearance. SARS-CoV-2 was detected in the nasopharyngeal and oropharyngeal swab samples by the RT-PCR method. Additional workup for malignancy, autoimmune disease, and other infections yielded negative results. Systemic corticosteroids and oxygen therapy were administered as she developed hypoxic respiratory failure. In addition, she received packed cell transfusion in view of hemolysis. Following corticosteroid and other supportive therapy, she recovered and was discharged well.

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